The question of whether heterocyclic amines (HAs) in cooked meats could be associated with idiopathic cardiomyopathies was raised by studies showing that cynomolgus monkeys chronically treated with 2-amino-3- methylimidazo[4,5-f]quinoline (IQ) for carcinogenicity testing had elevated levels of DNA adducts in the heart and developed foci of cardiac myocyte necrosis. We developed models to investigate mechanisms of HA- induced cardiotoxicity. Primary cultures of fetal myocytes were exposed to IQ, PhIP, or the activated forms of these carcinogens N-hydroxy-IQ and N-hydroxy-PhIP. LDH leakage increased in proportion to the dose of the N-hydroxylamine; however, little toxicity was seen with the parent amines. Electron microscopy revealed that cells treated with the N-hydroxylamines had swollen and irregular mitochondria and fewer organelles. DNA adducts, measured by the 32-P-postlabeling method, appeared to correlate with the degree of toxicity with each compound. The toxic effects of heterocyclic amines were also evaluated in rats given IQ or PhIP (100 mg/kg, p.o. 10x). Light microscopic and ultrastructural cardiac abnormalities were present in seven of eight rats exposed to IQ or PhIP. Whereas control animals had a normal cardiac morphology, carcinogen-treated animals had foci of chronic inflammation with myocyte necrosis, myofibrillar dissolution and disarray, and dilation of T-tubules. These results suggest that, in addition to being carcinogenic, the food mutagens may play a role in cardiac degeneration. The results from in vitro studies implicate the N-hydroxylamines in the cardiotoxicity of the HA-food mutagens. Studies on the possible protective effects of N-acetylcysteine and alpha-tocopherol are underway. The possible contribution of HA-induced oxidative damage in the myocardium is being pursued.
